Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
Sheffield Institute for Translational Neurosciences, University of Sheffield, Sheffield S10 2HQ, UK.
Int J Mol Sci. 2020 Feb 12;21(4):1225. doi: 10.3390/ijms21041225.
In the absence of lymphatics, fluid and solutes such as amyloid-β (Aβ) are eliminated from the brain along basement membranes in the walls of cerebral capillaries and arteries-the Intramural Peri-Arterial Drainage (IPAD) pathway. IPAD fails with age and insoluble Aβ is deposited as plaques in the brain and in IPAD pathways as cerebral amyloid angiopathy (CAA); fluid accumulates in the white matter as reflected by hyperintensities (WMH) on MRI. Within the brain, fluid uptake by astrocytes is regulated by aquaporin 4 (AQP4). We test the hypothesis that expression of astrocytic AQP4 increases in grey matter and decreases in white matter with onset of CAA. AQP4 expression was quantitated by immunocytochemistry and confocal microscopy in post-mortem occipital grey and white matter from young and old non-demented human brains, in CAA and in WMH. Results AQP4 expression tended to increase with normal ageing but AQP4 expression in severe CAA was significantly reduced when compared to moderate CAA ( = 0.018). AQP4 expression tended to decline in the white matter with CAA and WMH, both of which are associated with impaired IPAD. Adjusting the level of AQP4 activity may be a valid therapeutic target for restoring homoeostasis in the brain as IPAD fails with age and CAA.
在没有淋巴管的情况下，液体和溶质（如淀粉样蛋白-β（Aβ））沿着脑毛细血管和动脉壁的基膜从脑内排出 - 壁内动脉周围引流（IPAD）途径。随着年龄的增长，IPAD 会失效，不溶性 Aβ 会沉积在脑内和 IPAD 途径中形成脑淀粉样血管病（CAA）；液体在白质中积聚，反映在 MRI 上的高信号（WMH）。在脑内，星形胶质细胞对液体的摄取受水通道蛋白 4（AQP4）的调节。我们假设 CAA 发病时，星形胶质细胞 AQP4 的表达在灰质中增加，在白质中减少。通过免疫细胞化学和共聚焦显微镜，在年轻和老年非痴呆人类大脑的枕叶灰质和白质、CAA 和 WMH 中定量测定 AQP4 的表达。结果 AQP4 的表达随着正常衰老而趋于增加，但与中度 CAA 相比，严重 CAA 中的 AQP4 表达显著降低（=0.018）。AQP4 的表达随着 CAA 和 WMH 在白质中趋于下降，这两者都与 IPAD 受损有关。调整 AQP4 活性水平可能是恢复脑内稳态的有效治疗靶点，因为随着年龄的增长和 CAA 的发生，IPAD 会失效。
